T he E2F family of transcription factors (E2Fs) plays an important role in the regulation of cell proliferation and apoptosis and includes 6 structurally related E2F proteins (E2F1 through 6). E2Fs function as heterodimers with members of the DP family (DP-1 and DP-2) to transactivate or repress gene expression and play important roles in regulating both cell proliferation and antiproliferative processes such as apoptosis and senescence. 1 Atherosclerosis represents a defective reparative process in response to repeated injuries to the vessel wall. 2 Central to the resulting inflammatory reaction are proinflammatory cytokines, bacterial and viral products, and reactive oxygen intermediates, all of which activate nuclear factor kappa-B (NFB), which controls the transcription of over 100 genes that encode mediators of innate immune and inflammatory responses. 3 Among these induced genes are leukocyte adhesion molecules, metalloproteinases (MMPs), and proinflammatory cytokines, including tumor necrosis factor-␣ (TNF␣) and interleukin-6 (IL-6), which, in turn, can activate NFB. 4 Hence, NFB not only promotes the recruitment and activation of inflammatory cells, but also serves as a central switch within a positive feedback loop that regulates the expression of proinflammatory factors in the development of atherosclerosis. In addition, NFB works in concert with other transcription factors, activator protein-1 (AP-1) in particular, to activate the expression of pro-atherosclerotic genes 5 . In this context, atherosclerosis can be viewed as an inflammatory process that is critically dependent on the transcriptional activation of cytokine genes under the control of NFB and other transcription factors.
See p 2707The relevance of NFB to atherosclerosis is supported by numerous in vitro and in vivo studies. For example, activated NF and its regulated inflammatory mediators, such as cytokines, inducible NO synthase, and leukocyte adhesion molecules, have been detected in macrophages, smooth muscle cells, and endothelial cells in human atherosclerotic plaques but not in healthy vessels. 6 -8 Pathogenically important factors, such as reactive oxygen species involved in low-density lipoprotein oxidation, and components of microorganisms such as Chlamydia pneumoniae, can directly activate NFB in cells isolated from atherosclerotic plaques. 9,10 Furthermore, NFB serves as a signaling molecule in apoptosis transduction pathways, resulting in increased turnover of vascular cells located in atherosclerotic plaque caps, which then renders such plaques vulnerable to rupture, contributing to the development of unstable coronary syndromes 4 . Moreover, NFB has been implicated in the pathophysiology of myocardial ischemia-reperfusion injury, ischemic preconditioning, and heart failure, as well as noncardiovascular diseases, such as autoimmune arthritis, glomerulonephritis, asthma, lung fibrosis, septic shock, and carcinogenesis. 11 Inhibition of NFB nuclear translocation (and therefore activity), and probably of other transcription fac...